Process for Preparing Primary Intermediates for Dyeing Keratin Fibers

ABSTRACT

A process has been developed for preparing 2-methoxymethyl-1,4-benzenediamine (IV-a), other compounds of formula (IV), and the salts thereof, all of which may be used as primary intermediates in compositions for dyeing keratin fibers.

FIELD OF THE INVENTION

The present invention relates to a process for preparing primaryintermediates for dyeing keratin fibers. More particularly, theinvention relates to a process for preparing2-methoxymethyl-1,4-benzenediamine (IV-a), other compounds of formula(IV), and the salts thereof.

BACKGROUND OF THE INVENTION

Primary intermediates are used in compositions for dyeing keratinfibers. Known primary intermediates include2-methoxymethyl-1,4-benzenediamine (IV-a), other compounds of formula(IV), and the salts thereof.

Known processes of preparing 2-methoxymethyl-1,4-benzenediamine (IV-a),other compounds of formula (IV), and the salts thereof have yield andcost deficiencies. Therefore, there is a need for an industriallyapplicable, less expensive, and higher yielding process to synthesize2-methoxymethyl-1,4-benzenediamine (IV-a), other compounds of formula(IV), and the salts thereof.

SUMMARY OF THE INVENTION

According to one embodiment of the invention, there is provided aprocess for the preparation of 2-methoxymethyl-1,4-benzenediamine(IV-a), other compounds of formula (IV), and the salts thereofcomprising (a) performing a carbonyl reduction of a compound of formula(I) to prepare a compound of formula (II); (b) performing anetherification of the compound of formula (II) to prepare a compound offormula (III); and (c) performing a hydrogenation of the compound offormula (III) to prepare a compound of formula (IV):

wherein R¹, R², and R³ are substituents selected from the groupconsisting of:

a) C-linked substituents selected from the group consisting of:

-   -   i. alkyl groups;    -   ii. aryl groups; and    -   iii. substituents selected from the group consisting of COOA¹,        CONA¹, CONA¹COA², C(═NA¹)NA¹A², and CN;        -   wherein the C-linked substituents comprise from 1 to about            10 carbon atoms and from 0 to about 5 heteroatoms selected            from the group consisting of O, F, Cl, N, P, Si, and            mixtures thereof;

b) S-linked substituents selected from the group consisting of SA¹,SO₂A¹, SO₃A¹, SSA¹, SOA¹, SO₂NA¹A², SNA¹A², and SONA¹A²;

c) O-linked substituents selected from the group consisting of OA¹,ONA¹A²;

d) N-linked substituents selected from the group consisting of NA¹A²;(NA¹A²A³)⁺, NA¹SA², NO₂;

e) halogens selected from the group consisting of F, Cl, Br, and I;

f) hydrogen; and

g) mixtures thereof;

-   -   wherein A¹, A², and A³ are alkyl groups comprising from 1 to        about 10 carbon atoms and from 0 to about 5 heteroatoms selected        from the group consisting of O, F, Cl, N, P, Si, and mixtures        thereof;        wherein R⁵ is an alkyl group; and        wherein R⁶ and R⁷ are selected from the group consisting of        hydrogen, alkyl groups, aminoalkyl groups, hydroxyalkyl groups,        and mixtures thereof.

This and other features, aspects, and advantages of the presentinvention will become evident to those skilled in the art from a readingof the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

In all embodiments of the present invention, all percentages are byweight of the total composition, unless specifically stated otherwise.All ratios are weight ratios, unless specifically stated otherwise. Allranges are inclusive and combinable. The number of significant digitsconveys neither a limitation on the indicated amounts nor on theaccuracy of the measurements. All numerical amounts are understood to bemodified by the word “about” unless otherwise specifically indicated.Unless otherwise indicated, all measurements are understood to be madeat 25° C. and at ambient conditions, where “ambient conditions” meansconditions under about one atmosphere of pressure and at about 50%relative humidity. All such weights as they pertain to listedingredients are based on the active level and do not include carriers orby-products that may be included in commercially available materials,unless otherwise specified.

The term “comprising,” as used herein, means that other steps and otheringredients which do not affect the end result can be added. This termencompasses the terms “consisting of” and “consisting essentially of.”Compositions and methods/processes of the present invention cancomprise, consist of, and consist essentially of the elements andlimitations of the invention described herein, as well as any of theadditional or optional ingredients, components, steps, or limitationsdescribed herein.

The terms “include,” “includes,” and “including,” as used herein, aremeant to be non-limiting and are understood to mean “comprise,”“comprises,” and “comprising,” respectively. It should be understoodthat every maximum numerical limitation given throughout thisspecification includes every lower numerical limitation, as if suchlower numerical limitations were expressly written herein. Every minimumnumerical limitation given throughout this specification will includeevery higher numerical limitation, as if such higher numericallimitations were expressly written herein. Every numerical range giventhroughout this specification will include every narrower numericalrange that falls within such broader numerical range, as if suchnarrower numerical ranges were all expressly written herein.

The process for the preparation of 2-methoxymethyl-1,4-benzenediamine(IV-a), other compounds of formula (IV), and the salts thereof comprises(a) performing a carbonyl reduction of a compound of formula (I) toprepare a compound of formula (II); (b) performing an etherification ofthe compound of formula (II) to prepare a compound of formula (III); and(c) performing a hydrogenation of the compound of formula (III) toprepare a compound of formula (IV).

In an embodiment, the carbonyl reduction, then etherification, and thenhydrogenation may be performed successively. In another embodiment, thecarbonyl reduction, then hydrogenation, and then etherification may beperformed successively.

I. Carbonyl Reduction

Carbonyl reduction may be performed on a compound of formula (I) toprepare a compound of formula (II). R¹, R², R³, R⁶, and R⁷ are asdefined previously, may be independently selected, and may be identicalor different. Carbonyl reduction may be performed in the presence of acarbonyl reducing agent, a carbonyl reduction catalyst, and/or asolvent.

The carbonyl reducing agent may be selected from the group consisting ofhydrazine, hydrazine hydrate, H₂, LiAlH₄, LiBH₄, DIBAL-H, NaBH₄,NaCNBH₃, B₂H₆, BH₃/THF, sodium hydrosulfite, sodium sulfide, andmixtures thereof.

The carbonyl reduction catalyst may be selected from the groupconsisting of Raney nickel, nickel, palladium, Lindlar' s catalyst,cobalt, copper chromite, platinum, platinum oxide, rhenium, tin(II)chloride, titanium(III) chloride, zinc, samarium, iron, ruthenium,iridium, rhodium, and mixtures thereof.

The solvent may be selected from the group consisting of water,petroleum ether, pentane, acetic acid, cyclopentane, hexane,cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether,dichloromethane, tetrahydrofuran, methyl-tetrahydrofuran,dimethylformamide, acetonitrile, dimethyl sulfoxide, n-butanol,isopropanol, n-propanol, ethanol, methanol, and mixtures thereof.

Carbonyl reduction may be carried out at a temperature of from about 0°C. to about 100° C., alternatively from about 50° C. to about 80° C.,alternatively at about 70° C.

In an embodiment, the formula indicated by formula (I) may be preparedby inserting a nitro function into anthranilic acid or compounds thereofin the presence of a nitrating agent and/or a solvent. The nitratingagent may be selected from the group consisting of nitric acid, fumingnitric acid, red fuming nitric acid, salts of nitric acid (i.e.potassium nitrate), and mixtures thereof.

II. Etherification

Etherification may be performed on the compound of formula (II) toprepare a compound of formula (III). R¹, R², R³, R⁵, R⁶, and R⁷ are asdefined previously, may be independently selected, and may be identicalor different.

Alkylation Reaction

Etherification may be performed by an alkylation reaction in thepresence of an alkylating agent, a phase transfer catalyst, a solvent,and/or a base. The reaction mixture may be homogeneous or heterogeneous,may have two or more liquid phases, and/or may have any combination ofliquid and solid phases.

The alkylating agent may be selected from the group consisting ofalcohols, derivatives of alcohols (i.e. methyl methanesulfonate),(C₁-C₄)—I, (C₁-C₄)—Br, (C₁-C₄)—Cl, Me₂SO₄, and mixtures thereof. In oneembodiment, the alkylating agent may be dimethyl sulfate.

The phase transfer catalyst may be selected from the group consisting ofammonium salts that include tetrapentylammonium bromide,tetraoctylammonium chloride, tetraoctylammonium bromide,tetrahexylammonium iodide, tetrahexylammonium chloride,tetrahexylammonium bromide, tetraheptylammonium bromide,tetraethylammonium tetrafluoroborate, tetraethylammonium chloride,tetraethyl ammonium bromide, tetradodecylammonium tetrafluoroborate,tetradodecylammonium chloride, tetradodecylammonium bromide,tetradecyl-trimethylammonium chloride, benzyltriethyl ammonium chloride,phenyl-trimethylammonium bromide, octyl-trimethylammonium bromide,octadecyl-trimethylammonium chloride, octadecyl-trimethylammoniumbromide, methyl-trioctylammonium iodide, and mixtures thereof. In oneembodiment, the phase transfer catalyst may be benzyltriethyl ammoniumchloride.

The solvent may be selected from the group consisting of water,petroleum ether, pentane, cyclopentane, hexane, cyclohexane, benzene,toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane,tetrahydrofuran, methyl-tetrahydrofuran, ethyl acetate, acetone,dimethylformamide, acetonitrile, dimethyl sulfoxide, n-butanol,isopropanol, n-propanol, ethanol, methanol, and mixtures thereof.

The base may be selected from the group consisting of sodium hydroxide,potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesiumhydroxide, barium hydroxide, aluminum hydroxide, ferrous hydroxide,ferric hydroxide, zinc hydroxide, lithium hydroxide, sodium bicarbonate,sodium carbonate, and mixtures thereof. In one embodiment, the base maybe sodium hydroxide.

Condensation Reaction

Etherification may also be performed by a condensation reaction in thepresence of a condensation catalyst and/or a solvent.

The condensation catalyst may be selected from the group consisting ofmineral acids, Lewis Acids, aluminum chloride, titaniumtetra-isopropoxide, and mixtures thereof.

The solvent may be selected from the group consisting of petroleumether, pentane, cyclopentane, hexane, acetic acid, cyclohexane, benzene,toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane,tetrahydrofuran, methyl-tetrahydrofuran, ethyl acetate, acetone,dimethylformamide, acetonitrile, dimethyl sulfoxide, n-butanol,isopropanol, n-propanol, ethanol, methanol, and mixtures thereof. In oneembodiment, the solvent may be methanol.

The condensation reaction may be carried out with an inert solventdiluent and/or with heating. The inert solvent diluent may be chosen toaid in the removal of water if it is capable of forming a low boilingazeotrope. In this case, the condensation reaction may be carried out atreflux using a Dean Stark trap to drain off the water as it is formedand distilled off with the azeotrope. The condensation reaction may alsobe carried out in the presence of one or more dehydrating agents whichmay either react with or physically bind with the water, therebyremoving the water from equilibria. The dehydrating agent may beselected from the group consisting of dicyclohexylcarbodiimide,molecular sieves, magnesium sulphate, and mixtures thereof.

III. Hydrogenation

Hydrogenation may be performed on the compound of formula (III) toprepare a compound of formula (IV). R¹, R², R³, R⁵, R⁶, and R⁷ are asdefined previously, may be independently selected, and may be identicalor different.

Hydrogenation may be performed in the presence of hydrogen, ahydrogenation catalyst, and/or a solvent. The hydrogenation catalyst maybe selected from the group consisting of Raney nickel, nickel,palladium, Lindlar's catalyst, cobalt, copper chromite, platinium,platinum oxide, rhenium, tin(II) chloride, titanium(III) chloride, zinc,samarium, iron and mixtures thereof. The hydrogen pressure may be in arange from about atmospheric pressure to about 2,000 psig, alternativelyfrom about 50 psig to about 60 psig.

The solvent may be selected from the group consisting of water,petroleum ether, pentane, cyclopentane, hexane, cyclohexane, benzene,toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane,tetrahydrofuran, methyl-tetrahydrofuran, ethyl acetate, acetone,dimethylformamide, acetonitrile, dimethyl sulfoxide, n-butanol,isopropanol, n-propanol, ethanol, methanol. and mixtures thereof. In anembodiment, the solvent may be ethyl acetate.

In an embodiment, the compound of formula (IV) may be transformed intothe salt of formula (V) in the presence of mHZ and a solvent. R¹, R²,R³, R⁵, R⁶, and R⁷ are as defined previously, may be independentlyselected, and may be identical or different.

HZ is an acid having an acid proton “H.” “Z” represents the rest of themolecule. For example if HZ═HCl, then Z═Cl. The symbol “m” is the numberof moles of the acid. HZ may be selected from the group consisting ofD,L-malic acid, L-malic acid, D-malic acid, hydrochloric acid,hydrobromic acid, citric acid, acetic acid, lactic acid, succinic acid,tartaric acid, sulfuric acid, and mixtures thereof; and m may be ½, 1,3/2, or 2.

Protecting Groups

In an embodiment, a protecting group may be used when performing theabove process. Protecting groups are widely used in chemistry and oneskilled in the art would determine the appropriate step during theprocess to remove the protecting group in order to reach compounds offormula (IV). General explanations and uses of protecting groups aredescribed in “Greene's Protective Groups in Organic Synthesis” by PeterG. M. Wuts, Theodora W. Greene, Wiley-Interscience; 4th edition (Oct.30, 2006) and in “Protecting Groups” by Philip J. Kocienski, Thieme,Stuttgart; Auflage: 3rd Revised edition (Feb. 14, 2005).

IV. Synthesis of 2-Methoxymethyl-1,4-Benzenediamine

Compounds of formula (IV) include 2-methoxymethyl-1,4-benzenediamine(IV-a). The process described above can be utilized to synthesize2-methoxymethyl-1,4-benzenediamine (IV-a). The process may comprise:

a) reducing the carbonyl group of 5-nitroanthranilic acid (I-a) toprepare 2-amino-5-nitrobenzyl alcohol (II-a);

b) performing the etherification of 2-amino-5-nitrobenzyl alcohol (II-a)to prepare 2-methoxymethyl-4-nitroaniline (III-a); and

c) hydrogenating 2-methoxymethyl-4-nitroaniline (III-a) to prepare2-methoxymethyl-1,4-benzenediamine (IV-a).

EXAMPLES

The following examples illustrate the present invention:

Example 1 1. Synthesis of 2-Hydroxymethyl-4-Nitroaniline (II-a)

5-Nitroanthranilic acid (5.0 g, 27.45 mmol) is dissolved in THF (100 mL)and 1 M borane/THF complex (55 mL, 54.9 mmol) is added. The mixture isheated to reflux for 1 h. Analysis by TLC indicates complete consumptionof starting material. The volatiles are removed in vacuo and the residueis dissolved in ethyl acetate (150 mL). The organic phase is washed with1 N HCl, saturated NaHCO₃, and saturated NaCl. Evaporation provides 10.8g (98%) of a dark brown oil product which is used directly in the nextreaction; ¹H-NMR (500 MHz, CDCl₃); δ 4.61 (s, 2 H), 6.62 (s, 1 H), 8.01(m, 2 H).

2. Synthesis of 2-Methoxymethyl-4-Nitroaniline (III-a)

2-Hydroxymethyl-4-nitroanilne (1.0 g, 5.75 mmol) is suspended inpetroleum ether (10 mL). Sodium hydroxide solution (50%, 618 mg, 15.46mmol) and benzyltriethylammonium chloride (20 mg) are added withstirring. Dimethyl sulfate (728 uL, 7 7 mmol) is added and the reactionmixture is stirred at room temperature for 16 hours. Dichloromethane (50mL) and water (25 mL) are added, and the layers are separated. Theorganic layer is washed with saturated NaHCO₃ and evaporated affording440 mg of 2-methoxymethyl-4-nitroaniline (III-a) in 82% purity.

3. Synthesis of 2-Methoxymethyl-1,4-Benzenediamine (IV-a)

Into a Parr hydrogenation bottle previously purged with argon, areplaced a solution of 2-methoxymethyl-4-nitroaniline (5.0 g, 27.5 mmol)in ethyl acetate (50 mL) and 0.25 g of 10% palladium on carbon. Thebottle is mounted on a Parr shaker and hydrogenation is carried outunder 50-60 psig (64.7-74.7 psi or 446-515 kPa) of hydrogen pressure.The pressure is carefully monitored for hydrogen uptake and additionalhydrogen is introduced to keep the pressure above 50 psig. Thehydrogenation is carried out for 3.5 hours after which the catalyst isremoved by vacuum filtration. The filtrate is concentrated to about 25mL and toluene (25 mL) is added to precipitate the product, which iscollected by vacuum filtration and dried at 60° C. under vacuum. Theproduct yield is 4.5 g; ¹H-NMR (500 MHz, DMSO-d₆) δ 3.23 (s, 3 H), 4.11(s, 2 H), 4.21 (s, 2 H), 4.24 (s, 2 H), 6.33 (dd, 1 H), 6.37 (d, 1 H),6.41 (d, 1 H).

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

Every document cited herein, including any cross referenced or relatedpatent or application, is hereby incorporated herein by reference in itsentirety unless expressly excluded or otherwise limited. The citation ofany document is not an admission that it is prior art with respect toany invention disclosed or claimed herein or that it alone, or in anycombination with any other reference or references, teaches, suggests,or discloses any such invention. Further, to the extent that any meaningor definition of a term in this document conflicts with any meaning ordefinition of the same term in a document incorporated by reference, themeaning or definition assigned to that term in this document shallgovern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover all such changes and modifications that are within thescope of this invention.

What is claimed is:
 1. A process for the preparation of2-methoxymethyl-1,4-benzenediamine (IV-a), other compounds of formula(IV), and the salts thereof comprising: a. performing a carbonylreduction of a compound of formula (I) to prepare a compound of formula(II); b. performing an etherification of the compound of formula (II) toprepare a compound of formula (III); and c. performing a hydrogenationof the compound of formula (III) to prepare a compound of formula (IV);

wherein R¹, R², and R³ are substituents selected from the groupconsisting of: i. C-linked substituents selected from the groupconsisting of: a) alkyl groups; b) aryl groups; and c) substituentsselected from the group consisting of COOA¹, CONA¹, CONA¹COA²,C(═NA¹)NA¹A², and CN; wherein the C-linked substituents comprise from 1to about 10 carbon atoms and from 0 to about 5 heteroatoms selected fromthe group consisting of O, F, Cl, N, P, Si, and mixtures thereof; ii.S-linked substituents selected from the group consisting of SA¹, SO₂A¹,SO₃A¹, SSA¹, SOA¹, SO₂NA¹A², SNA¹A², and SONA¹A²; iii. O-linkedsubstituents selected from the group consisting of OA¹, ONA¹A²; iv.N-linked substituents selected from the group consisting of NA¹A²;(NA¹A²A³)⁺, NA¹SA², NO₂; v. halogens selected from the group consistingof F, Cl, Br, and I; vi. hydrogen; and vii. mixtures thereof; whereinA¹, A², and A³ are alkyl groups comprising from 1 to about 10 carbonatoms and from 0 to about 5 heteroatoms selected from the groupconsisting of O, F, Cl, N, P, Si, and mixtures thereof; wherein R⁵ is analkyl group; and wherein R⁶ and R⁷ are selected from the groupconsisting of hydrogen, alkyl groups, aminoalkyl groups, hydroxyalkylgroups, and mixtures thereof.
 2. The process according to claim 1further comprising inserting a nitro function into anthranilic acid orcompounds thereof in the presence of a nitrating agent and a solvent toprepare the compound of formula (I):


3. The process according to claim 1, wherein the carbonyl reduction ofthe compound of formula (I) into the compound of formula (II) isperformed in the presence of a carbonyl reducing agent, a carbonylreduction catalyst, and a solvent.
 4. The process according to claim 3,wherein the carbonyl reducing agent is selected from the groupconsisting of hydrazine, hydrazine hydrate, H₂, LiAlH₄, LiBH₄, DIBAL-H,NaBH₄, NaCNBH₃, B₂H₆, BH₃/THF, sodium hydrosulfite, sodium sulfide, andmixtures of thereof.
 5. The process according to claim 3, wherein thecarbonyl reduction catalyst is selected from the group consisting ofRaney nickel, nickel, palladium, Lindlar' s catalyst, cobalt, copperchromite, platinium, platinum oxide, rhenium, tin(II) chloride,titanium(III) chloride, zinc, samarium, iron and mixtures thereof. 6.The process according to claim 1, wherein the etherification of thecompound of formula (II) into the compound of formula (III) is performedby alkylation in the presence of an alkylating agent, a phase transfercatalyst, a solvent, and a base.
 7. The process according to claim 6,wherein the alkylating agent is selected from the group consisting ofmethanol, (C₁-C₄)—I, (C₁-C₄)—Br, (C₁-C₄)—Cl, Me₂SO₄, and mixturesthereof.
 8. The process according to claim 6, wherein the phase transfercatalyst is selected from the group consisting of ammonium salts thatinclude tetrapentylammonium bromide, tetraoctylammonium chloride,tetraoctylammonium bromide, tetrahexylammonium iodide,tetrahexylammonium chloride, tetrahexylammonium bromide,tetraheptylammonium bromide, tetraethylammonium tetrafluoroborate,tetraethylammonium chloride, tetraethylammonium bromide,tetradodecylammonium tetrafluoroborate, tetradodecylammonium chloride,tetradodecylammonium bromide, tetradecyl-trimethylammonium chloride,benzyltriethyl ammonium chloride, phenyl-trimethylammonium bromide,octyl-trimethylammonium bromide, octadecyl-trimethylammonium chloride,octadecyl-trimethylammonium bromide, methyl-trioctylammonium iodide, andmixtures thereof.
 9. The process according to claim 6, wherein the baseis selected from the group consisting of sodium hydroxide, potassiumhydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide,barium hydroxide, aluminum hydroxide, ferrous hydroxide, ferrichydroxide, zinc hydroxide, lithium hydroxide, sodium bicarbonate, sodiumcarbonate, and mixtures thereof.
 10. The process according to claim 1,wherein the etherification of the compound of formula (II) into thecompound of formula (III) is performed by a condensation reaction in thepresence of a condensation catalyst and a solvent.
 11. The processaccording to claim 10, wherein the condensation catalyst is selectedfrom the group consisting of mineral acids, Lewis Acids, aluminumchloride, titanium tetra-isopropoxide, and mixtures thereof.
 12. Theprocess according to claim 1, wherein the hydrogenation of the compoundof formula (III) into the compound of formula (IV) is performed in thepresence of hydrogen, a hydrogenation catalyst, and a solvent.
 13. Theprocess according to claim 12, wherein the hydrogenation catalyst isselected from the group consisting of Raney nickel, nickel, palladium,Lindlar's catalyst, cobalt, copper chromite, platinium, platinum oxide,rhenium, tin(II) chloride, titanium(III) chloride, zinc, samarium, ironand mixtures thereof.
 14. The process according to claim 1 furthercomprising transforming the compound of formula (IV), including2-methoxymethyl-1,4-benzenediamine (IV-a), into the salt of formula (V)in the presence of mHZ and a solvent:


15. The process according to claim 14, wherein HZ is selected from thegroup consisting of D,L-malic acid, L-malic acid, D-malic acid,hydrochloric acid, hydrobromic acid, citric acid, acetic acid, lacticacid, succinic acid, tartaric acid, sulfuric acid, and mixtures thereof;and wherein m=1.
 16. The process according to claim 1, wherein thecarbonyl reduction, then etherification, and then hydrogenation areperformed successively.
 17. The process according to claim 1, whereinthe carbonyl reduction, then hydrogenation, and then etherification areperformed successively.
 18. The process according to claim 1 comprising:a. reducing a carbonyl group of 5-nitroanthranilic acid (I-a) to prepare2-amino-5-nitrobenzyl alcohol (II-a):

b. performing the etherification of 2-amino-5-nitrobenzyl alcohol (II-a)to prepare 2-methoxymethyl-4-nitroaniline (III-a):

and c. hydrogenating 2-methoxymethyl-4-nitroaniline (III-a) to prepare2-methoxymethyl-[1,4]-benzenediamine (IV-a):


19. The process according to claim 18, wherein reducing the carbonylgroup is performed at a temperature from about 50° C. to about 80° C.20. The process according to claim 18, wherein the etherification isperformed by phase transfer alkylation.